The area under the curve represents QALYs measured by QoL-AGHDAutility during 6 years of treatment, where A depicts general population values, B gain during GH replacement, and C values for patients with GHD without treatment. The value 1 on the y-axis stands for full health, and 0 for death.

Methods and subjects

Study design

The study consisted of twoparts, the first of which estimated utilities for the QoL-AGHDA based on data obtained from a survey of the general population in England and Wales (E&W). The secondpart used utility-weighted QoL-AGHDA data to calculate QoL changes in patients during treatment in relation to normative population values, also examining the impact of demographic and patients’ clinical characteristics.

General population – deriving utilities

EQ-5D, 12 a generic measure of QoL developed by the EuroQoL group, defines a total of 243 health states for each of which there is a corresponding score based on values obtained from the UK general population, using TTO methods.13 Based on these data a set of utilities for all health states described by the EQ-5D has been estimated.

The model demonstrated an adjusted R2 of 0·42. Each regression coefficient, bi, represents the utility weight for the corresponding QoL-AGHDA item and when aggregated across all 25 items, this yields an estimate of the utility-weighted QoL-AGHDA, referred to here as QoL-AGHDAutility.

Results

The mean observed EQ-5Dindex in the general population [0·83 (SD 0·214) in men and 0·81 (SD 0·228) in women] reflectedclosely the estimated QoL-AGHDAutility[0·83 (SD 0·127) in men and 0·83 (SD 0·141) in women].

Patient characteristics

The patient cohort consisted of 894 participants (53% women) from E&W who were followed up for 1 to 6 years. Mean observation time was 3·4 (1·74) years. All patients had GHD confirmed by relevantstimulation tests and were not treated with GH for a minimum of 6 monthsprior to entry.

The mean age of the patients was 40 (SD 16·5) years at diagnosis of GHD, and 45 (SD 14·3) years at entry into KIMS. Men were slightlyolder than women at both time points: at diagnosis men were aged 41 (SD 17·1) and were women 40 (SD 15·9), and at entry into KIMS men were 45 (SD 14·7) and women were 44 (SD 13·9).

There were significant (P < 0·0001) positivecorrelations between PGWB scores at baseline, last observation and change in PGWB score and corresponding measures of QoL-AGHDAutility (r = 0·68, r = 0·68 and r = 0·42, respectively). These highly significant correlations indicate consistency between both measures; that is, if psychological well-being as measured by PGWB improves, QoL-AGHDAutility also shows improvement and viceversa.

Comparison of QoL-AGHDA

QoL measured by QoL-AGHDAutility in patients before commencement of GH treatment differed significantly from the expected values calculated from the sample of the general population [0·67 (SD 0·174) vs. 0·85 (SD 0·038), P < 0·0001], constituting a mean deficit of –0·19 (SD 0·168). There was also a significant difference in the mean QoL-AGHDAutility deficit for men [–0·16 (SD 0·170)] and women [–0·21 (SD 0·162)] (P < 0·001). The main improvement occurred during the first year of observation when the QoL-AGHDAutility deficit was reduced to –0·07 (SD 0·163) (P < 0·001) in the total cohort and to –0·07 (SD 0·160) (P < 0·001) in men and –0·08 (SD 0·170) (P < 0·001) in women. The difference between gendersdisappeared after the first year of GH treatment. The same was true for the deficit at the last reported visit: men –0·07 (SD 0·160) and women –0·08 (SD 0·170). Despite a dramatic improvement during the first year of observation that was maintained during the whole follow-up period, patients’ QoL-AGHDAutility remained significantly different (P < 0·001) from those reported by the general population (line A in Fig. 1).

Patient subgroups

In the last step of this study, QoL-AGHDAutility at baseline and response to GH treatment were evaluated with respect to demographic and clinical characteristics.

Age

QoL-AGHDAutility was negatively correlated with age both at baseline (r = ndash 0·23; P < 0·0001) and at the latest reported visit (r = ndash 0·25; P < 0·0001), meaning that QoL-AGHDAutilitydeteriorated with advancing age (Fig. 2). However, the mean total QoL-AGHDAutility gain and also well as the mean gain per year were similar through all the age groups (data not shown).

Fig. 2

95% confidence intervals for mean QoL-AGHDAutility at baseline (broken line) and at the last reported visit (continuous line) by age group.

Primary aetiology

There were differences in QoL-AGHDAutility between aetiology groups at baseline and at the last reported visit. Patients with GHD due to pituitary adenoma, both nonfunctioning and secreting, had the lowest QoL-AGHDAutility at both time points (Table 1). However, the primary cause for GHD had no influence on the response to treatment measured by total QoL-AGHDAutility gain and mean gain per year.

Previous treatment

Neither previous surgery nor irradiation had an impact on QoL-AGHDAutility at any time point, and did not influence response to GH (data not shown).

Disease onset

QoL-AGHDAutility scores were higher in patients with CO disease than with adult-onset (AO) both at baseline [0·75 (SD 0·173) vs. 0·64 (SD 0·166), P < 0·001] and at the last reported visit [0·82 (SD 0·167) vs. 0·76 (SD 0·170), P < 0·001]. However, patients with CO-GHD gained less than AO patients with regard to the total gain [0·18 (SD 0·488) vs. 0·35 (SD 0·559)] and to the mean gain per year [0·05 (SD 0·117) vs. 0·09 (SD 0·123)] (Fig. 3).

Fig. 3

95% confidence intervals for mean QoL-AGHDAutility at baseline and during GH replacement therapy in patients with childhood-onset and adult-onset GHD.

When controlled for age and gender using multiple regression analysis, patients with CO disease continued to demonstrate significantly higher QoL-AGHDAutility at baseline and responded to a lesser extent to GH treatment than patients with AO (P < 0·0001).

Extent of hypopituitarism

The number of additional to GH pituitary hormone deficits showed no significant correlation with any of the QoL-AGHDAutilityparameters (Fig. 4). Similarly, patients with isolated GHD demonstrated equivalentlevels of deficit in QoL-AGHDAutility at baseline and comparable gain during GH treatment in comparison with patients with multiple pituitary hormone deficiency.

Fig. 4

95% confidence intervals for mean QoL-AGHDAutility at baseline (broken line) and during GH replacement therapy (continuous line) in patients by number of pituitary deficits.

Comorbidities

There was a significant impact of reported comorbidities on all QoL parameters. Patients who reported health problems in addition to GHD (n = 513) had lower QoL-AGHDAutility mean scores at baseline [0·63 (SD 0·167), P < 0·001] and at the last reported visit [0·75 (SD 0·174), P < 0·001] compared to patients with no reported comorbidities (n = 381) [0·71 (SD 0·172) and 0·81 (SD 0·159), respectively]. At the same time, patients with comorbidities responded better to GH treatment in terms of QoL-AGHDAutility[mean 0·36 (SD 0·565) for total gain (P < 0·002) and 0·10 (SD 0·124) for gain/year (P < 0·004)] compared to patients with no reported comorbidities [0·25 (SD 0·520) and 0·07 (SD 0·119), respectively].

The other methodological issue was the choice of independent variables entered into the regression analysis (the QoL-AGHDA summary score, all individual QoL-AGHDA items or selected items identified in stepwise forward regression analysis). As the final model yielded an adjusted R2 of 0·42, whereas in a stepwise forward regression analysis and in the model with the QoL-AGHDA summary score the adjusted R2assumed the value of 0·40, we decided to choose the model that fitted our data best.

The novelty of our approach is to apply utilities derived from the QoL-AGHDA to the patient population and to evaluate QALY change in a clinical context as a function of treatment response together with patients’ demographic and clinical characteristics.

Cost–utility analysis based on QALY change is the most widely recognized method in pharmacoeconomic evaluation, and QoL-AGHDA was investigated by the NationalInstitute for Health and Clinical Excellence (NICE) as a potentialsource of outcome data for such an evaluation. Nevertheless, the final conclusion of NICE was that there was a lack of evidence to construct a plausible cost–utility model that would allow cost per QALY to be generated.22 Our study, despite its observationalnature, which is an obviouslimitation, provides a methodology for monitoring QALY changes over the course of GH replacement in comparison with the age- and gender-matched population values. Patients showed a profound QoL deficit before treatment, and significant improvement during follow-up. This pattern is very similar to the pattern of response in QoL measured by QoL-AGHDA23 (a dramatic improvement during the first year and a subsequent steadyincrease during the ensuing years of treatment). The main difference is that the patients’ utilities, contrary to the QoL-AGHDA scores, remained different from the population values during prolonged follow-up. This discrepancy might be related to the nature of both measures, as QoL-AGHDA directly records problems linked to GHD, whereas the utility-weighted index is based on a scoringsystem that reflects a broaderspectrum of health as experienced by the general population. As the duration of follow-up varied from patient to patient, the change in QoL-AGHDAutility was calculated as a total gain per follow-up but also as a gain per year. By doing this, we were able to present results in a more comprehensive way. It is worth noting that the high correlation between PGWB scores and QoL-AGHDAutilityconstitutes additional evidence for consistency of the methodology.

As expected, QoL expressed as utilities in younger patients was better (demonstrated by a higher value), which corresponds to manyreports on QoL, both for the population and the patients.27, 28 It is noteworthy that the QoL gain was not affected by age and that older patients benefitequally from GH treatment compared to the younger patients in terms of utilities, supporting previous observations on the QoL response to GH in older patients with hypopituitarism.29

Overall, despite some differences at baseline, clinical parameters did not have an impact on response to treatment; all patients presented similar total and annual QoL-AGHDAutility gain. The only exception was patients with CO-GHD and patients with comorbidities. The former responded to GH to a lesser extent. Nevertheless, it should be remembered that patients with CO-GHD were characterized by higher levels of QoL-AGHDAutility at baseline, so it might be speculated that their response was driven by the extent of initialpathology. It has been confirmed that patients with less impairment in QoL at baseline demonstrate minor response.30 The same explanationmay apply to the observation that patients who reported more comorbidities and thus lower QoL-AGHDAutility at baseline gained more QoL-AGHDAutility during treatment.

The other limitation of our study relates to the assumption that GH treatment has no differential impact on mortality. QALYs consist of two components, quality (utility) and quantity (duration of life), and both contribute to the final value of the index. The increased mortality rate in hypopituitary patients with untreated GHD has been proven.31, 32 However, despite promising observations, there is still no final evidence on the beneficial effect of GH replacement on mortality rates. It should be noted that any final QALY estimates should incorporate treatment effects on patients’ survival together with the QoL-AGHDAutility gain presented in this paper. Assuming that GH treatment reverses, at leastpartly, the increased mortality associated with hypopituitarism, the total QALY gain should account for additional life years.

In conclusion, our study reports a newpossibility of translating QoL-AGHDA into utilities. We have shown that this derived QoL-AGHDAutility index, with its main application to cost–utility analysis, efficiently monitors treatment effects in patients with GHD. The study confirmed the QoL-AGHDAutility deficit before treatment and a similar QoL-AGHDAutility gain, despite baseline discrepancies, in all patients observed after commencement of GH replacement.

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